DESCRIPTION (Verbatim from the applicant's abstract) The body's response to injury and surgical stress involves the coordinated elaboration of a number of pro-inflammatory and anti-inflammatory mediators which function to prevent the spread of invading organisms, minimize tissue injury, repair damaged tissues, and restore homeostasis and vital organ function. Among the earliest mediators produced in response to injury and infection are catecholamines, corticosteroids, and glucagon. The mechanisms by which glucagon regulates glucose homeostasis have been well characterized, while the ability of glucagon to alter other metabolic pathways has not been extensively studied. The expression of nitric oxide synthase in hepatocytes is important in the response of the liver to infection because NO from the inducible nitric oxide synthase (iNOS) contributes to sepsis-induced hepatic injury and hepatic dysfunction. Our preliminary data demonstrate that glucagon inhibits hepatocyte nitric oxide (NO) synthesis by inhibiting the expression of iNOS in response to pro-inflammatory stimuli in both in vitro and in vivo models of sepsis. The reduction in iNOS expression with glucagon is associated with decreased LPS-mediated hepatic injury and decreased LPS-mediated hepatic dysfunction. In this proposal, we will identify the mechanisms responsible for the regulation of this critical hepatocyte pathway by glucagon. We will identify the mechanisms involved in the transcriptional regulation of iNOS by glucagon (AIM D, the regulation by glucagon of post-transcriptional effects on iNOS expression (AIM II), and the second messenger signal transduction systems responsible for these events (AIM III). By defining the mechanisms involved in the regulation of iNOS expression by glucagon, we will enhance our understanding of the cellular events that constitute the body's response to injury, stress, and infection. These insights will contribute to uncovering the basic cellular mechanisms involved in multiple organ dysfunction and may lead to potential therapeutic approaches.